McCune-Albright syndrome (MAS) is a non-genetic disorder in which affected subjects show a variety of seemingly unrelated abnormalities including polyostotic fibrous dysplasia, pigmented skin lesions cafe-au-lait spots), and autonomous hyperfunction of various endocrine organs including gonads, anterior pituitary, thyroid, and adrenal cortex. The endocrine abnormalities lead to precocious puberty, gigantism, hyperthyroidism, and hypercortisolism. The cause of this sporadic disorder has been completely enigmatic, but speculations have centered on a defect in signal transduction leading to endocrine hyperfunction. The distribution of skin lesions has also suggested the possibility of a somatic mutation acquired early, in embryogenesis and affecting only a subset-of cells (mosaicism). Since a G protein mutation could plausibly explain the endocrine manifestations, we searched for and found mutations of the Gs-alpha gene that lead to constitutive activation of the Gs protein. These mutations were found in a mosaic distribution; notably, mutant gene was undetectable in normal-appearing portions of endocrine glands, but was present at heterozygous levels in neoplastic portions of endocrine tissue. Our studies suggest that MAS is caused by a somatic mutation in the Gs-alpha gene occurring early in development and found in a mosaic distribution.